Synthesis, characterization and urease inhibition of a novel acetylhydroxamate-coordinated oxovanadium(V) complex with hydrazone ligand

Article abstract of DOI:10.1016/j.inoche.2014.04.008

The first example of a novel acetylhydroxamate-coordinated oxovanadium(V) complex with hydrazone ligand has been prepared and structurally characterized. The urease inhibitory activity of the complex was assayed, and the molecular docking study was performed. The complex has strong urease inhibitory activity. The introduction of acetylhydroxamate ligand as functional urease inhibitory group may increase the activity of the complex.

Full text of DOI:10.1016/j.inoche.2014.04.008

Synthesis,
characterization and urease inhibition of
a
novel
acetylhydroxamate-coordinated oxovanadium(V) complex with hydra-
zone ligand
Yang Huo, Yu-Ting Ye, Xiao-Shan Cheng, Zhong-Lu You
PII:
DOI:
Reference:
S1387-7003(14)00170-1
doi: 10.1016/j.inoche.2014.04.008
INOCHE 5547
To appear in:
Inorganic Chemistry Communications
Received date:
Revised date:
Accepted date:
12 January 2014
8 April 2014
10 April 2014
Please cite this article as: Yang Huo, Yu-Ting Ye, Xiao-Shan Cheng, Zhong-Lu You, Syn-
thesis, characterization and urease inhibition of a novel acetylhydroxamate-coordinated
oxovanadium(V) complex with hydrazone ligand, Inorganic Chemistry Communications
(2014), doi: 10.1016/j.inoche.2014.04.008
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ACCEPTED MANUSCRIPT
Synthesis,
characterization
and
urease
inhibition
of
a
novel
acetylhydroxamate-coordinated oxovanadium(V) complex with hydrazone ligand
Yang Huoa, Yu-Ting Yea, Xiao-Shan Chenga, Zhong-Lu Youa,b,
a
Department of Chemistry and Chemical Engineering, Liaoning Normal University,
Dalian 116029, P. R. China
b
State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing
210093, P.R. China
____________________________________________________________________
Abstract
The first example of a novel acetylhydroxamate-coordinated oxovanadium(V) complex
with hydrazone ligand has been prepared and structurally characterized. The urease
inhibitory activity of the complex was assayed, and the molecular docking study was
performed. The complex has strong urease inhibitory activity. The introduction of
acetylhydroxamate ligand as functional urease inhibitory group may increase the
activity of the complex.
Keywords: Hydrazone; Acetylhydroxamate; Oxovanadium complex; Crystal structure;
Urease inhibition
Urease is a nickel-containing metalloenzyme that catalyzes the hydrolysis of urea to
form ammonia and carbamate [1,2]. The resulting carbamate spontaneously
decomposes to yield a second molecule of ammonia and carbon dioxide. High
concentration of ammonia arising from the reaction, as well as the accompanying pH
elevation, has important negative implications in medicine and agriculture [3–5].
Control of the activity of urease through the use of inhibitors could counteract these
negative effects. In recent years, urease inhibitors play an important role in the
treatment of the infections caused by urease producing bacteria [6]. Inhibitors of urease
can be broadly classified into two species: (1) organic compounds, such as
acetohydroxamic acid, humic acid, and 1,4-benzoquinone [7–8]; (2) heavy metal ions,
such as Cu2+, Zn2+, Pd2+, and Cd2+ [10,11]. Considering the metal complexes are a kind
 Corresponding author.
E-mail address: youzhonglu@lnnu.edu.cn (Zhong-Lu You).
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of versatile enzyme inhibitors [12], we have recently reported the urease inhibitory
activities of a number of complexes with Schiff bases [13-15]. The results show that
some Schiff base copper(II) complexes have potential urease inhibitory activities.
Vanadium complexes have been widely investigated in biological chemistry, especially
for their insulin-enhancing activities [16-18]. During the search of literature, we found
that vanadium(IV) complexes bearing hydrazone ligands also possess interesting
urease inhibitory activities [19]. Acetylhdroxamic acid (AHA) is a commercial urease
inhibitor. The obvious short-coming of this substance is that it is very soluble in water
and readily to lose from soil. From the point of coordination chemistry, AHA is also a
potential bidentate ligand. Can the binding of AHA to oxovanadium complex with
hydrazone ligand bearing effective urease inhibition? If yes, it can not only increase
the utilization rate of AHA, but also form more complicated urease inhibitors. Based
on this consideration, in this paper, a novel acetylhdroxamate (AH) coordinated
oxovanadium(V)
complex,
[VO2L(AH)]
(H2L
Scheme
=
N'-(5-bromo-2-hydroxybenzylidene)-3-nitrobenzohydrazide;
1),
was
synthesized and structurally characterized. The urease inhibitory activity of the
complex was investigated from both experimental and molecular docking analysis
[20].
H
N
Br
NO2
N
O
OH
Scheme 1. H2L.
The yellow crystalline product of the hydrazone ligand H2L was prepared by
reaction of equimolar quantities of 5-bromosalicylaldehyde with
3-nitrobenzohydrazide in ethanol and subsequent evaporation of the solvent. Yield:
91%. Anal. Calc. for C14H10BrN3O4: C 46.2, H 2.8, N 11.5%. Found: C 46.0, H 2.8, N
11.6%. Selected IR data (KBr, cm-1): ν 1617 (s, C=N).
An ethanolic solution (20 mL) of H2L (0.5 mmol, 0.182 g) and AHA (0.5 mmol,
0.038 g) mixed together was added with stirring to an ethanolic solution (20 mL) of
VO(acac)2 (0.5 mmol, 0.133 g). The mixture was stirred at room temperature for 30
min to give deep brown solution. Brown block-shaped single crystals suitable for
X-ray diffraction were formed by slow evaporation of the solution in air for a few days.
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Yield: 68%. Anal. Calc. for C18H18BrN4O8V: C 39.4, H 3.3, N 10.2%. Found: C 39.3,
H 3.4, N 10.1%. Selected IR data (KBr, cm-1): 3435 (br, m, O–H), 1603 (s, C=N), 969
(m, V=O).
Diffraction intensities for the complex were collected at 298(2) K using a Bruker
SMART CCD detector with Mo-Kα radiation (λ = 0.71073 Å). The collected data were
reduced using SAINT program [21], and multi-scan absorption corrections were
performed using SADABS program [22]. The structure was solved by direct method
and refined against F2 by full-matrix least-squares method using SHELXTL [23]. All
non-hydrogen atoms were refined anisotropically. The amino H was located from a
difference Fourier map and refined isotropically, with N–H distance restrained to
0.90(1) Å. The remaining hydrogen atoms were placed in calculated positions and
constrained to ride on their parent atoms.
The measurement of Helicobacter pylori urease inhibitory activity was carried out
for three parallel times. Helicobacter pylori (ATCC 43504; American Type Culture
Collection, Manassas, VA) was grown in brucella broth supplemented with 10%
heat-inactivated horse serum for 24 h at 37 ºC under microaerobic conditions (5% O2,
10% CO2, and 85% N2). The method of preparation of Helicobacter pylori urease by
Mao was followed [24]. Briefly, broth cultures (50 mL, 2.0 × 108 CFU mL–1) were
centrifuged (5000 g, 4 ºC) to collect the bacteria, and after washing twice with
phosphate-buffered saline (pH = 7.4), the Helicobacter pylori precipitation was stored
at –80 ºC. Helicobacter pylori was returned to room temperature, and after addition of
3 mL of distilled water and protease inhibitors, sonication was performed for 60 s.
Following centrifugation (15,000 g, 4 ºC), the supernatant was desalted through
SephadexG-25 column (PD-10 columns, Amersham–Pharmacia Biotech, Uppsala,
Sweden). The resultant crude urease solution was added to an equal volume of glycerol
and stored at 4 ºC until use in the experiment. The mixture, containing 25 μL (4U) of
Helicobacter pylori urease and 25 μL of the test compound, was pre-incubated for 3 h
at room temperature in a 96-well assay plate. Urease activity was determined by
measuring ammonia production using the indophenol method as described by
Weatherburn [25].
Molecular docking of the complex into the three-dimensional X-ray structures of
Helicobacter pylori urease structure (entry 1E9Z in the Protein Data Bank) was carried
out using the AUTODOCK 4.0 software as implemented through the graphical user
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interface AutoDockTools (ADT 1.4.6).
The graphical user interface AUTODOCKTOOLS was employed to setup the
enzymes: all hydrogens were added, Gasteiger charges were calculated and nonpolar
hydrogens were merged to carbon atoms. The Ni initial parameters are set as r = 1.170
Å, q = +2.0, and van der Waals well depth of 0.100 kcal/mol [26]. The 3D structures of
ligand molecule were saved in Mol2 format with the aid of the program MERCURY.
The partial charges of Mol2 file were further modified by using the ADT package
(version 1.4.6) so that the charges of the nonpolar hydrogens atoms assigned to the
atom to which the hydrogen is attached. The resulting file was saved as a pdbqt file.
The AUTODOCKTOOLS program was used to generate the docking input files. In
the docking a grid box size of 60 × 60 × 70 points in x, y, and z directions was built,
the map was centered on Ni3001 atom in the catalytic site of the protein. A grid
spacing of 0.375 Å and a distances-dependent function of the dielectric constant were
used for the calculation of the energetic map. 100 runs were generated by using
Lamarckian genetic algorithm searches. Default settings were used with an initial
population of 50 randomly placed individuals, a maximum number of 2.5 × 106 energy
evaluations, and a maximum number of 2.7 × 104 generations. A mutation rate of 0.02
and a crossover rate of 0.8 were chosen. The results of the most favorable free energy
of binding were selected as the resultant complex structure.
The hydrazone ligand H2L and the oxovanadium(V) complex were readily prepared
at room temperature. The molar conductance value of the complex measured in
acetonitrile at concentration of 10–3 M is 27 Ω–1 cm2 mol–1, indicating the
non-electrolytic nature of the complex [27].
The hydrazone ligand has stretching bands attributed to C=O, C=N, C–OH and NH
at 1651, 1617, 1153 and 1236, and 3251 cm–1, respectively. The complex exhibits
typical bands at 969 cm–1, which is assigned to the V=O vibration [28]. The band due
to νC=O was absent in the complex, and new C–O stretch appeared at 1272 cm–1. This
suggests occurrence of keto-imine tautomerization of the ligand during complexation.
The νC=N absorption observed at 1617 cm–1 in the free hydrazone ligand shifted to 1603
cm–1 for the complex upon coordination to the V atom. The weak peaks in the low
wave numbers at 490 and 586 cm–1 may be attributed to V–O and V–N bonds in the
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complex.
The molecular structure of the complex is shown in Figure 1. X-ray crystallography
[29] reveals that the asymmetric unit of the complex contains a mononuclear
oxovanadium(V) species and an ethanol molecule. The coordination geometry around
the V atom is highly distorted octahedral. The hydrazone ligand behaves in a tridentate
manner in which the phenolate O, imino N, and enolate O atoms occupy a meridional
plane. The acetylhydroxamate ligand behaves in a bidentate manner, and coordinates to
the V atom through the deprotonated hydroxyl O atom and the carbonyl O atom. The
equatorial plane of the octahedral coordination is defined by O1, N1, O2 and O6 atoms,
and the axial positions are occupied by O2 and O7 atoms. The distortion of the
octahedral geometry can be evidenced by the coordinate bond lengths and angles. The
V1–O5 bond is significantly longer than the other V–O bonds, yet, it is not uncommon
for such complexes [30-32]. The equitorial atoms show high degree of planarity, with
mean deviation from plane of 0.020(3) Å. The V atom deviates from the least-squares
plane defined by the four equitorial atoms by 0.290(1) Å. All the bond lengths in the
complex are comparable to those observed in similar vanadium(V) complexes [30-32].
The angular distortion in the octahedral environment around V comes from the five-
and six-membered chelate rings taken by the hydrazone ligand. For the same reason,
the trans angle significantly deviates from the ideal value of 180°. The hydrazone
ligand in is approximately planar, with the dihedral angle between the two benzene
rings of 3.8(3)°.
In the crystal structure of the complex, mononuclear oxovanadium complex
molecules are linked by ethanol molecules through intermolecular N4–H4···O8 and
O8–H8···O5i hydrogen bonds [N4–H4 = 0.90(1) Å, H4···O8 = 1.823(6) Å, N4···O8 =
2.716(3) Å, N4–H4···O8 = 172°; O8–H8 = 0.82 Å, H8···O5i = 2.076(7) Å, O8···O5i =
2.862(3) Å, O8–H8···O5i = 161°; symmetry code for i: x – 1, y, z], to form 1D chains
running down the a-axis direction (Figure 2). In addition, there are weak π···π
interactions among the benzene rings of the hydrazone ligand and the
V1-O2-C8-N2-N1 and V1-O5-C16-N4-O6 chelate rings.
[Insert Figures 1 and 2 about here]
Differential thermal (DT) and thermal gravimetric analyses (TGA) were conducted
to examine the stability of the complex (Figure 3). There are four steps of
decomposition. The first step started at 140 °C and ended at 159 °C, with a weight loss
of 8.5%, which is caused by the loss of the ethanol molecule (8.4%). Actually, the
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complex was first decomposed at 160 °C and completed at 490 °C. It is difficult to
ascribe the remaining three steps of decomposition. The weight loss of these three
steps is 77%, corresponding to the loss of the hydrazone and acetylhdroxamate ligands
and the formation of V2O5. The total weight loss of 85.5% is close to the idea value of
84.3%.
[Insert Figure 3 about here]
The percentage inhibition at concentration of 100 μM for the complex is 96.2 ± 4.5.
The acetohydroxamic acid was used as a reference [6] with percentage of inhibition of
87.3 ± 3.3. The IC50 value of 8.3 ± 1.6 μM for the complex is superior to that of AHA
(37.2 ± 1.7 μM), and also stronger than that of vanadyl sulfate (196 ± 7 μM) and the
vanadium complexes we reported previously [30, 33]. As a detailed comparison, the
hydrazone ligand itself has no activity at the concentration of 100 μM. The vanadium
complex formed by the reaction of the hydrazone ligand and VO(acac)2 without the
addition of AHA has effective urease inhibition (100 μM, 72%; IC50 = 21.5 μM), yet, it
is obvious weaker than the complex reported herein. Lineweaver-Burk plots of
1/absorbance versus 1/urea were used to determine the type of enzyme inhibition
(Figure 4). The plots show that the complex inhibits the urease in a mixed mode.
[Insert Figure 4 about here]
The enzyme surface model and the weak interactions of the complex with the
enzyme are shown in Figures 5 and 6, respectively. It is obvious that the complex
molecule is well filled in the active pocket of the urease, with the nitrobenzene and
acetylhydroxamate segments inserted in the hole. The nitro group of the ligand is much
close to the two Ni atoms of the active center of the urease. The complex forms weak
interactions with ASP165, ASN168, HIS138, KCX219, ASP362, ALA365, GLY279,
MET366, ARG338 and CYS321 of the urease. As a result, the docking score (–12.8) of
the complex is much lower than that of AHA (–5.0).
[Insert Figures 5 and 6 about here]
Conclusion
In summary, the present paper reports the first example of a novel
acetylhydroxamate
coordinated
oxovanadium(V)
complex
with
N'-(5-bromo-2-hydroxybenzylidene)-3-nitrobenzohydrazide. The complex show strong
urease inhibitory activity, with IC50 value of 8.3 ± 1.6 μM. The complex may be used
in the treatment of infections caused by urease producing bacteria, which deserves
further study.
6

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Acknowledgement
This work was financially supported by the Natural Science Foundation of China
(Project No. 20901036).
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Figure 1. A perspective view of the molecular structure of the complex with the atom
labeling scheme. Thermal ellipsoids are drawn at the 30% probability level. Selected
bond lengths (Å) and bond angles (°): V1-O1 1.854(3), V1-O2 1.950(2), V1-O5
2.235(2), V1-O6 1.856(2), V1-O7 1.583(3), V1-N1 2.085(3); O7-V1-O1 100.2(1),
O7-V1-O6 96.5(1), O1-V1-O6 104.2(1), O7-V1-O2 99.2(1), O1-V1-O2 153.7(1),
O6-V1-O2 91.0(1), O7-V1-N1 99.2(1), O1-V1-N1 84.4(1), O6-V1-N1 160.4(1),
O2-V1-N1 75.1(1), O7-V1-O5 172.2(1), O1-V1-O5 83.3(1), O6-V1-O5 75.8(1),
O2-V1-O5 79.8(1), N1-V1-O5 88.1(1).
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Figure 2. Molecular packing diagram of the complex, viewed along the axis-b direction.
Hydrogen bonds are shown as dashed lines.
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60
40
20
0
100
80
60
40
20
0
-20
-40
200
400
600
800
1000
Temperature (oC)
Figure 3. DT-TGA curve of the complex.
20
15
10
5
0
0.0
-0.3
-0.2
-0.1
0.1
0.2
0.3
1/urea mM-1
Figure 4. Lineweaver–Burk plot of inhibition of urease by the complex. ■ no complex
present. The straight line plots refer to the complex concentrations of 5.50 μg·mL-1 (●)
and 11.00 μg·mL-1 (▲).
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Figure 5. The receptor surface model of the complex for Helicobacter pylori urease.
The enzyme is shown as Surface. The complex is shown as sticks.
CYS321
ARG338
ASP165
MET366
GLY279
ALA365
ASN168
HI S138
Ni 1
Ni 2
ASP362
KCX219
Figure 6. Binding model of the complex with the active site of Helicobacter pylori
urease. Weak interactions are shown as dashed lines.
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Graphical Abstract
The first example of a novel acetylhydroxamate coordinated oxovanadium(V) complex
with hydrazone ligand was obtained. The complex show strong urease inhibitory
activity with IC50 value of 8.3 ± 1.6 μM.
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Highlights
► A novel acetylhydroxamate coordinated oxovanadium(V) complex was prepared. ► The
complex has been characterized by single crystal X-ray diffraction. ► Thermal stability was
studied. ► The complex show strong urease inhibitory activity.
16